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Neuraxial Anesthesia Reduces Lymphatic Flow: Proof-of-Concept in First In-Human Study

Hiller, Jonathan G. MBBS (Hons.), GCEpi, FANZCA*†‡; Ismail, Hilmy M. MD, FRCA, FFARCS(I), FANZCA*; Hofman, Michael S. MBBS (Hons), FRACP, FAANMS§; Narayan, Kailash MBBS, MD, PhD, FRANZCR‖¶; Ramdave, Shakher MBBS, MD, FRACP, FAANMS#; Riedel, Bernhard J. MD, FRCA, FANZCA, MBA, PhD*†

doi: 10.1213/ANE.0000000000001562
Chronic Pain Medicine
Free

Dilation of lymphatic vessels may contribute to iatrogenic dissemination of cancer cells during surgery. We sought to determine whether neuraxial anesthesia reduces regional lymphatic flow. Using nuclear lymphoscintigraphy, 5 participants receiving spinal anesthesia for brachytherapy had lower extremity lymph flow at rest compared with flow under conditions of spinal anesthesia. Six limbs were analyzed. Four limbs were excluded because of failure to demonstrate lymph flow (1 patient, 2 limbs), colloid injection error (1 limb), and undiagnosed deep vein thrombosis (1 limb). All analyzed limbs showed reduced lymph flow washout from the pedal injection site (range 62%–100%) due to neuraxial anesthesia. Lymph flow was abolished in 3 limbs. We report proof-of-concept that neuraxial anesthesia reduces lymphatic flow through a likely mechanism of sympathectomy.

Published ahead of print September 16, 2016.

From the *Department of Cancer Anaesthesia, Perioperative and Pain Medicine, Peter MacCallum Cancer Centre, Australia; Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, Australia; PhD candidate, Monash University, Clayton, Melbourne, Australia; §Department of Diagnostic Imaging, Peter MacCallum Cancer Centre, Australia; Department of Radiation Oncology and Cancer Imaging, Peter MacCallum Cancer Centre, Australia; Department of Obstetrics and Gynaecology, University of Melbourne, Australia; and #Department of Nuclear Imaging and PET, Monash Medical Centre, Australia.

Published ahead of print September 16, 2016.

Accepted for publication July 11, 2016.

Funding: This work was supported by a grant received from the Australian and New Zealand College of Anaesthetists (N13/002) (JH).

The authors declare no conflicts of interest.

Reprint will not be available from the authors.

Address correspondence to Jonathan G. Hiller, Department of Cancer Anaesthesia, Perioperative and Pain Medicine, Peter MacCallum Cancer Centre, 305 Grattan St, Melbourne, 3000, Australia. Address e-mail to jonathan.hiller@petermac.org.

The lymphatic circulation, judged the “second circulation” by cancer researchers, increases drainage to regional lymph nodes after a surgical incision and associated edema.1

Smooth muscle arrangements—lymphangions—envelop distal lymphatic channels and receive stimulatory sympathetic neural innervation to produce peristalsis that propels lymph flow centrally from the extremities.2

Perioperative neuraxial anesthesia is associated with improved cancer outcomes,3 particularly in lower limb cancer surgery,4 and researchers have hypothesized a reduction in iatrogenic tumor cell dissemination through neuraxial anesthesia’s sympathectomy to be contributory.5

We sought to determine proof-of-concept that patients’ lower limb lymphatic drainage was reduced by spinal anesthesia.

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METHODS

Our institution’s clinical research committee approved the study (Project Number 09/15, Human Research Ethics Committee Peter MacCallum Cancer Centre; Australian Clinical Trials Registry, ACTRN12612001162808) before the obtainment of written, informed consent from participating patients. This study adhered to the Consolidated Standards of Reporting Trials guidelines.

Recruited patients received cervical/prostate carcinoma brachytherapy under long-acting spinal anesthesia as standard care. Using lymphoscintigraphy, lymph flow at baseline (without spinal anesthesia) was measured 7–10 days before a second lymphoscintigram performed following their brachytherapy: patients acted as their own controls.

Exclusion criteria were lymphedema or clinical pelvic lymphadenopathy, complex regional pain syndrome, lower limb surgery, body mass index >30 kg/m2 (due to difficult lymphoscintigram interpretation), diabetes mellitus, and α/β-adrenergic receptor therapy.

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Lymphoscintigraphy

Technetium-99m antimony sulfide colloid (99mTc-ASC, 0.25 mL) was injected subdermally in the first web space of both feet simultaneously, and lymphoscintigraphy commenced for quantitative measurement of lymph flow from foot to groin. 99mTc-ASC’s 5.2-hour biological half-life ensured clearance within 24 hours. Identical lymphoscintigram technique was performed for all studies; all patients were rested on the imaging table with legs immobilized but not compressed. Ambient room temperature was standardized (22°C).

The second lymphoscintigram, under spinal anesthesia, was performed after patients’ brachytherapy. Spinal anesthesia consisted of an intrathecal injection of 25 mg of ropivacaine and 22.5 μg of clonidine using a 25-gauge spinal needle at the L3-4/L4-5 interspace. Information was collected on heart rate, blood pressure, and intraoperative sympathomimetic use. After brachytherapy, patients were transferred to the imaging department. Confirmation of dermatome block higher than T96 was made before lymphoscintigraphy commencement; in all patients this occurred <140 minutes after spinal anesthesia initiation.

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Imaging and Analysis

Dynamic quantitative image acquisition utilized a gamma camera (2 independent heads, Philips Skylight) and performed 60 minutes after injection allowing simultaneous measurement of colloid clearance (foot) and colloid uptake (pelvis). A static mid-abdomen to feet image was also acquired at 120 minutes. Limbs were analyzed individually per protocol.

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Statistical Analysis

The primary outcome was the comparison of percentage colloid washout at 60 minutes in baseline versus spinal lymphoscintigrams. Percentages were used to enable inter-limb comparison. The study aimed to recruit 10 patients but was ceased after successful demonstration of proof-of-concept.

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RESULTS

Baseline characteristics of the study population are shown in Table 1. Of 5 recruited patients (3 women, 2 men), 6 limbs were analyzed. Four limbs were excluded: patient 1 (2 limbs; absent lymph flow on baseline or spinal lymphoscintigrams 2 hours after colloid injection), patient 2 (colloid injection error), and patient 3 (undiagnosed deep vein thrombosis).

Table 1.

Table 1.

Lymph flow reduction due to spinal blockade was demonstrated in all limbs, ranging from 0.48% to 61.27% (Table 2). Spinal anesthesia reduced lymph flow by 62%–100%; in 3 instances, there was no detectible lymph flow from the foot 4 hours after the institution of neuraxial block.

Table 2.

Table 2.

Figure.

Figure.

Figure illustrates the rapid lower limb colloid transit lost under conditions of spinal anesthesia and minimal accumulation of colloid in the inguinal lymph nodes.

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DISCUSSION

This study sought to determine the influence of spinal anesthesia and associated sympathectomy on lower limb lymphatic flow—a previously unstudied area of research. The observation of a reduction in lymphatic flow of radioisotope-labeled colloid from the injection site in all analyzed limbs demonstrated proof-of-concept.

The likely mechanism for our observations is the loss of normal sympathetically mediated peristaltic lymphangion contraction—the predominant means of lymph flow propulsion at rest.7 The sympathectomy, induced by spinal anesthesia, reduced the efferent outflow from the thoracic sympathetic chain at levels T9-L1 (the sympathetic supply to lower limbs).6 The observation of blood pressure and heart rate reduction in all patients (and dermatome block higher than T9) was used as an indicator of sympathetic blockade. Our findings reflect those of animal studies where sympathetic stimulation accelerated lymph flow and sympathetic blockade abolished lymph flow.8

Our observations have implications for future research into the perioperative behavior of lymphatics during cancer surgery. Induced, temporary sympathectomy to the tumor microenvironment of residual disease may be of therapeutic advantage given the role of neural adrenergic nervous system in stimulating lymphangiogenesis,1 lymph channel dilation, and tumor growth.9 Furthermore, surgical inflammation increases lymph flow, with passive opening of lymphatic pores to limit tissue edema and assist clearance of perilymphatic cellular debris.10 Detached (isolated) tumor cells from the surgical site are cleared by lymphatic systems. Plausibly, a reduction in perioperative lymphatic flow and isolated tumor cell release from the surgical site through the use of spinal anesthesia may confer oncological benefit.

Given the unexpected magnitude of effect in this exploratory study, the demonstration of proof-of-concept and the acknowledged inconvenience, and considerable discomfort for patients in study participation, the study was terminated prematurely. A limitation of the study remains the small sample size. Because of variability in lymph flow, and to minimize confounding, the study design ensured patients acted as their own biological controls: lymph flow was compared before/after spinal anesthesia specific to the same limb. The coadministered intrathecal clonidine could conceivably affect lymphatic flow, although this effect would have been uniform across all patients. Although lymphoscintigraphy commenced >60 minutes after the administration of sympathomimetics, these agents are a potential confounder, although their influence would manifest as a reduction in the observed effect.

We report proof-of-concept for spinal anesthesia achieving a reduction in lymphatic flow. In addition to contributing a novel understanding of the physiologic, neural regulation of lymphatic flow in humans, the results may have implications for the provision of anesthesia for cancer resection surgery, sentinel node biopsy, and the lymphedema of complex regional pain syndrome. The clinical relevance of our findings to impact cancer recurrence patterns requires further study.

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ACKNOWLEDGMENTS

We thank the following for their valuable contribution to the conceptualization and conduct of the study: Mr. Mark Scalzo, Professor Rod Hicks, Dr. David Bernshaw, Dr. Beauregard Jean-Mathieu, Mr. Peter Eu (colloid preparation).

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DISCLOSURES

Name: Jonathan G. Hiller, MBBS (Hons.), GCEpi, FANZCA.

Contribution: Protocol development, ethics application and study registration, study funding, manuscript preparation.

Name: Hilmy M. Ismail, MD, FRCA, FFARCS(I), FANZCA.

Contribution: Concept and protocol development, ethics application, study funding, study conduct, manuscript preparation.

Name: Michael S. Hofman, MBBS (Hons), FRACP, FAANMS.

Contribution: Protocol development (colloid dosimetry), study funding, imaging, and preparation of results.

Name: Kailash Narayan, MBBS, MD, PhD, FRANZCR.

Contribution: Protocol development.

Name: Shakher Ramdave, MBBS, MD, FRACP, FAANMS.

Contribution: Protocol development (colloid dosimetry), ethics application.

Name: Bernhard J. Riedel, MD, FRCA, FANZCA, MBA, PhD.

Contribution: Study funding, manuscript preparation.

This manuscript was handled by: Honorio T. Benzon, MD.

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